WO2018012773A1 - 울다비오시드 a 화합물을 함유하는 항염증 조성물 - Google Patents

울다비오시드 a 화합물을 함유하는 항염증 조성물 Download PDF

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WO2018012773A1
WO2018012773A1 PCT/KR2017/006932 KR2017006932W WO2018012773A1 WO 2018012773 A1 WO2018012773 A1 WO 2018012773A1 KR 2017006932 W KR2017006932 W KR 2017006932W WO 2018012773 A1 WO2018012773 A1 WO 2018012773A1
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inflammatory
composition
compound
diseases
paragraph
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PCT/KR2017/006932
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English (en)
French (fr)
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서원호
김익휘
차병윤
김호
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주식회사 엘큐바이오
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/60—Sugars, e.g. mono-, di-, tri-, tetra-saccharides

Definitions

  • the present invention is Ulda bioseed isolated from the extract of Ulm davidiana Planch.
  • composition containing A (Uldavioside A) compound as an active ingredient.
  • Inflammation is a hostess against wounds, microbial infections, etc.
  • Macrophages are the most representative immune cells that control inflammatory reactions. Activated macrophages are tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), progetaglandin E2 (PGE 2 ) and NO. secrete a variety of inflammation-related factors, such as nitric oxide and reactive oxygen species (Laskin, DL, et al, 2011). On the other hand, overexpression of these inflammation-related factors is associated with rheumatoid arthritis, osteoporosis, sepsis, and vascular disease. , Cancer light
  • Ubnus davidiana Planch is a dried bark and root bark of the cork layer of the locust tree (t // mj «davidiana var. Japonica Nakai), belonging to the ulmaceae family. Toxic, swelling, arthritis, gastric ulcer, gastrointestinal disease, etc., has been reported to have an excellent effect on expectorants, anticancer, wound healing drugs and inflammation (Duke JA, 1985).
  • ⁇ -sitosterol phytosterol, stimasterol, tannin, starch, polysaccharide, etc.
  • composition of the present invention is different because no Uldabioside A compound is listed.
  • Compound A Yes, but no anti-inflammatory effect.
  • Bon The object of the invention was to isolate from the extract of Ulmus davidiana Planch
  • the present invention provides a compound of Ulvidioside A of Formula 1
  • the anti-inflammatory composition may be a pharmaceutical composition for the prevention or treatment of inflammatory diseases including a pharmaceutically acceptable carrier.
  • the inflammatory diseases include inflammatory growth diseases, atherosclerosis, inflammatory collagen vascular diseases, glomerulonephritis, bedsores, ' inflammatory skin diseases, sarcoidosis, retinitis, gastritis, hepatitis, enteritis, arthritis, tonsillitis, pharyngitis, bronchitis, pneumonia, It can be selected from the group consisting of pancreatitis, sepsis, degenerative chronic inflammatory disease and nephritis.
  • composition is based on the total weight of the composition of
  • the composition may be a pharmaceutical composition formulated as an oral administration agent, a spraying agent, a gel, an ointment, a cream, or an external preparation.
  • the anti-inflammatory composition may be used as a food additive acceptable food.
  • the inflammatory diseases include inflammatory growth diseases, atherosclerosis, inflammatory collagen vascular diseases, glomerulonephritis, pressure sores, inflammatory skin diseases, sarcoidosis, retinitis gastritis, hepatitis, enteritis, arthritis, tonsillitis, pharyngitis, bronchitis, pneumonia, pancreatitis, It can be selected from the group consisting of sepsis, degenerative chronic inflammatory disease and nephritis.
  • the dietary supplement is based on the total weight of the composition of Ulda bioseed A compound.
  • 0.001-50% by weight may be contained.
  • the dietary supplement may be a dietary supplement formulated into tablets, capsules, pills, and liquids.
  • the present invention relates to an anti-inflammatory composition containing the uldabioside A compound of Formula 1 as an active ingredient.
  • the compound of Chemical Formula 1 can be synthesized according to a conventional method, can be prepared as a pharmaceutically acceptable salt, or can be separated and purified from the dermis extract.
  • the root bark is a dried bark and root bark of the bark of the bark (W / "davidiana var. Japonica Nakai) belonging to the ulaceae family.
  • the roots extract of the roots is water, lower alcohols of C1 to C4 or their
  • the mixed solution can be extracted as a solvent.
  • the C1 to C4 alcohols can be selected from the group consisting of methanol, propanol, isopropanol, butanol and isobutanol.
  • the compound separated from the root skin extract can be purified using column chromatography.
  • Addition chromatography can include silica gel column chromatography, HP-20 column chromatography, and HP-20 column chromatography.
  • the anti-inflammatory composition may be used for inflammatory diseases, including pharmaceutically acceptable carriers. It may be a prophylactic or therapeutic pharmaceutical composition.
  • the inflammatory disease is a disease caused by inflammation of the main lesion, inflammatory growth disease,
  • Atherosclerosis inflammatory collagen vascular disease, glomerulonephritis, pressure sores, inflammatory skin disease, sarcoidosis, retinitis, stomach, hepatitis, hepatitis, arthritis, tonsillitis, pharyngitis, bronchitis, pneumonia, pancreatitis, sepsis, degenerative chronic inflammation
  • sarcoidosis inflammatory collagen vascular disease
  • glomerulonephritis glomerulonephritis
  • pressure sores inflammatory skin disease
  • sarcoidosis retinitis
  • stomach hepatitis
  • hepatitis hepatitis
  • arthritis tonsillitis
  • pharyngitis bronchitis
  • pneumonia pancreatitis
  • sepsis degenerative chronic inflammation
  • Inflammatory growth disease is a disease that causes chronic inflammation alone, and may be ischemic growth disease, Crohn's disease, and intestinal diverticulum.
  • the pharmaceutical composition may contain 0.001 to 50% by weight, preferably 0.001 to 40% by weight, based on the total weight of the composition of davioside A compound.
  • the pharmaceutical compositions are oral formulations, external preparations, suppositories, and sterile injections of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, sprays, etc., in accordance with conventional methods.
  • Carriers, excipients, and diluents that may be included in the pharmaceutical composition may include lactose, textose, sucrose, solbi, manny, xili, erysme, malty, starch, Acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate,
  • Propyl hydroxybenzoate, talc, hemp; nem stearate, and mineral oil are used for the preparation.
  • diluents or excipients such as layering agents, bulking agents, binders, wetting agents, disintegrating systems, surfactants, etc. are used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may be used in the compounds of the invention of Uldabioside A; at least one excipient, for example, Prepared by mixing starch, calcium carbonate, sucrose or lactose, gelatin and the like.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid oral agents for oral use include suspensions, solvents, emulsions, and syrups, and various excipients besides the commonly used simple diluents, liquid paraffin, etc.
  • wetting agents may include sweeteners, fragrances, preservatives, etc.
  • Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-drying agents, suppositories.
  • Vegetable oils such as propylene glycol, polyethylene glycol, olive oil, and injectable esters such as ethyl oleate may be used.
  • suppositories include witepsol, macrogol,
  • Tween-61 cacao butter, laurin, glycerogelatin and the like can be used.
  • the pharmaceutical composition may be, but is not limited to, a pharmaceutical composition formulated as an oral dosage form, a spray, a gel, an ointment, a cream, or an external preparation.
  • the dosage of the pharmaceutical composition of the present invention will vary depending on the age, sex, weight of the subject to be treated, the severity of the particular disease or disease to be treated, the severity of the disease or pathology, the route of administration and the prescriber's judgment. Dose determination based on It is within the level of those skilled in the art, and generally the dosage is about 0.01 mg / kg / day
  • the preferred dosage is lmg / kg / day to 500 mg / kg / day. Dosing can be given once a day or multiple times. The above doses do not limit the scope of the present invention in any way.
  • the pharmaceutical composition of the present invention has various pathways in mammals such as rats, cattle, and humans.
  • the compounds of the present invention are toxic. It is a drug that can be used safely and for long-term use for the purpose of prevention because there is almost no side effect.
  • the anti-inflammatory composition may be a food additive acceptable food additive.
  • the dietary supplement is Uldabio: Seed A compound is added to the total dietary supplement weight.
  • the health functional food may be in the form of tablets, capsules, pills, or liquids, and to which the Uldabioside A compound of the present invention may be added, for example, various foods, beverages, Chewing gum, tea, vitamin complexes, and health functional foods.
  • the present invention relates to a composition for the prophylaxis or treatment of inflammatory diseases, which contains the extract of Jlmus davidiana Planch (Uldavioside A) as an active ingredient.
  • the Uldabioside A Compound of the Invention is Allergic and Inflammatory
  • Intestinal disease atherosclerosis, inflammatory collagen vascular disease, glomerulonephritis, inflammatory skin disease, sarcoidosis, retinitis, gastritis, hepatitis, enteritis, arthritis, tonsillitis, pharyngitis, bronchitis, pneumonia, pancreatitis, sepsis, bedsores, degenerative chronic inflammation disease It is expected to be easily used as a therapeutic or health food for various inflammatory diseases such as nephritis.
  • FIG. 1 is a cross-sectional view of an Ulviobioside A compound of the present invention.
  • TNF-a A
  • IL-1 B
  • NO C
  • FIG. 4 shows the treatment of uldabioside A compound with the present invention in inflammatory reaction caused by hypoxia.
  • the iNOS (A) and ICAM-1, MMP-2 and MMP-9 (B) expressions are shown.
  • FIG. 5 shows the results of treating the bed sores with creams containing dabioside A compound of the present invention.
  • A Treatment of bed sores after treatment for 14 days in 4 patients with antibiotic resistance or bed sores.
  • B shows the result of 30 days treatment for 4 patients with pressure sores that started to appear fascia, and
  • C showed treatment effect for 4 days with 4 patients with pressure sores that had begun fascia.
  • the root skin (fZ / m davidiana Planch) was purchased from a farm and used. After adding purified water 1 to 10 g of dried rooted skin, use a semi-continuous low temperature vacuum extractor.
  • FBS fetal bovine serum
  • DMEM Dulbecco's Modified Eagle's Medium
  • MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) assay method was used.
  • Inflammation-related factors NO (nitric oxide), TNF-a (tumor necrosis factor-a), and the anti-inflammatory effects of the treatment of the Uldabioside A compound of the present invention.
  • IL-1 (3) expression of IL-1 (3) (interleukin-1 (3)) was immediately determined using the corresponding enzyme-linked immunosorbent assay (ELISA) kit.
  • TNF-a 3A
  • IL-1 3B
  • NO 3C
  • the present amount was reduced depending on the treatment concentration of Uldabioside A compound of the present invention.
  • C70C12 and NIH3T3 cells cultured in Experimental Example 1 were dispensed in a 100cm plate to be 80% full and cultured overnight, and then treated with cells such that Uldabioside A compound became ⁇ and 20 ⁇ for 1 hour. After incubation, the cells were incubated for 24 hours in a hypoxic solution (1 1 ) 0 & chamber with 94% hydrogen, 5% carbon dioxide, and 1% oxygen to induce hypoxia, at which time no cells were treated. Cells that induced hypoxia and were not treated with the Uldabioside A compound of the present invention were used as negative controls. After 24 hours, the protein was recovered from each cell and the protein expression was confirmed by using the antibodies corresponding to iNOS, ICAM-1, MMP-2 and MMP-9 by Western blot method, and the results are shown in FIG. .
  • the Uldabioside A compound of the present invention is related to oxygen-induced inflammation.
  • Bed sores are pressured by constant or repetitive pressure in any part of the body.
  • tank white petrolatum 15 wt% cetostearyl alcohol 10 wt%
  • the Uldabioside A compound of the present invention was mixed with 175.9 g of lactose, 180 g of potato starch, and 32 g of colloidal silicic acid. After adding 10% gelatin solution to the mixture, the mixture was ground and passed through a 14 mesh body. The mixture was dried and purified from the mixture obtained by adding 160 g of potato starch, 50 g of active and 5 g of magnesium stearate .
  • Uldabioside of the present invention 1.28 mg of A compound, 522 mg of honey, 5 rag of thioctoamide amide, 10 mg of nicotinic acid amide, 3 rag of sodium riboflavin hydrochloride, 2 mg of pyridoxine hydrochloride, 30 rag of inosine, ortho acid : 50 mg, and water 200i. And the contents were prepared using the conventional method.

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Abstract

본 발명은 유근피(Ulmus davidiana Planch)추출물로부터 분리한 울다비오시드 A(Uldavioside A)화합물을 유효성분으로 함유하는 항염증 조성물에 관한 것이다. 보다 자세하게는 상기 울다비오시드 A 화합물이 염증성 사이토카인 및 염증 관련 인자들의 발현을 억제함으로써 항염증 활성을 나타내므로 염증성 질환의 예방 또는 치료용 조성물 및 염증성 질환의 개선용 건강기능식품으로 유용하게 이용 될 수 있다.

Description

명세서
발명의명칭:을다비오시드 A화합물을함유하는항염증조성물 기술분야
[1] 본발명은유근피 (ᅳ Ulm davidiana Planch)추출물로부터분리한울다비오시드
A(Uldavioside A)화합물을유효성분으로함유하는항염증조성물에관한 것이다.
배경기술
[2] 염증반응 (inflammation)은상처，미생물감염등에대항하는숙주의
방어기제에따른병리학적인기작에중요하지만,지속적이고과도한염증 반웅은조직의손상을유발하여비염，기관지염，간염，관절염등다양한질환을 유도하기도한다.특히，평균수명연장으로인한인구의노령화로그문제가 심각한퇴행성질환의경우，그병태생리가염증면역반응과밀접한관계가 있다는연구보고들이증가하고있어,염증반웅의기전및역할에대한관심이 급격하게증가하고있으며，염증치료를위한치료제개발에도관심이증가하고 있다.
[3] 대식세포는염증반웅을조절하는가장대표적인면역세포로서，활성화된 대식세포는 TNF-a(tumor necrosis factor-a), IL-6(interleukin-6), PGE2(prostaglandin E2), NO(nitric oxide), ROS(reactive oxygen species)등과같은다양한염증관련 인자를분비한다 (Laskin, D.L., et al, 2011).한편，이러한염증관련인자의 과발현은류마티스관절염.,골다공증,패혈증，혈관질환，암등을
유도한다 (Lawrence, T., et al., 2002).
[4] 유근피 (Ubnus davidiana Planch)는느롭나무과 (Ulmaceae)에속하는느롭나무( t//mj« davidiana var. japonica Nakai)의코르크층을벗긴수피및근피를건조한 것이다.한방에서유근피는맛이달고,무독하며，종창，관절염，위궤양，위장병 등에사용되고,거담，항암，상처치료약및염증에도탁월한효과가있다고 보고되어있다 (Duke J.A., 1985) 유근피중에존재하는천연물로서
β-시토스테를 (β-sitosterol),피토스테롤 (phytosterol),스티마스테롤 (stimasterol), 탄닌 (tannin),전분 (starch),다당류 (polysaccharide)등이존재한다.또한
진통작용을나타내는성분인프리델린 (friedelin)과
에피프리엔데라롤 (epifriendelalol),타락세롤 (taraxerol)등의분리 (Matsuzaki T., et al, 1985)와화학적조성에관한연구 (Duke J.A., 1985)등이많이이루어져 있으나유근피의다양한생리활성을연구한시도는아직까지거의이루어지지 않았다.
[5] 이:에，본발명자는유근피의추출물을함유하는항염증조성물을연구하는 과정에서，유근피추출물로부터분리된울다비오사드 A화합물이우수한 항염증활성을가지고있음을확인함으로써본발명을완성할수있었다. [6] 종래선행기술로서한국공개특허제 2000-0041190호에는유백피를포함하는 약제조성물의염증,상처와같은질환의예방및치료가기재되어있고， 한국공개특허제 2006-0078305호에는유근피를포함하는생약추출물을 함유하는항염효과를갖는화장료조성물이기재되어있어밌으나，
울다비오시드 A화합물이기재된바가없어본발명의구성과차이가있다.
[7] 또한，비특허문헌으로서 Son B.W., et al.은느롭나무에서분리한을다비오시드
A화합물이기재:되어있으나，항염증효과는기재된바가없다.
발명의상세한설명
기^적과제
[8] 본 :발명의목적은유근피 (Ulmus davidiana Planch)추출물로부터분리한
울다비오시드 A(Uldavioside A)화합물을유효성분으로함유하는항염증 조성물을'제공하는데에있다. :
과제해결수단
[9] 본발명은하기화학식 1의울다비오시드 A(Uldavioside A)화합물을
유효성분으로함유하는항염증조성물에관한것이다.
[10] [화학식 1]
Figure imgf000004_0001
[12] 상기항염증조성물은약학적으로허용가능한담체를포함하는염증성질환의 예방또는치료용약학적조성물일수있다.
[13] 상기염증성질환은염증성장질환,죽상동맥경화，염증성콜라겐혈관질환， 사구체신염,욕창， '염증성피부질환，유육종증,망막염，위염，간염，장염，관절염, 편도선염，인후염，기관지염，폐렴，췌장염，패혈증，퇴행성만성염증질환및 신장염으로이루어진군에서선택될수있다.
[14] 상기약학적조성물은을다비오시드 A화합물이조성물총중량에대하여
으001~50증량 %로함유될수있탸.
[15] 상기조성물은경구용투여제,스프레이제,겔제,연고제，크림제또는외용제로 제형화된약학적조성물일수있다.
[16] 또한,상기항염증조성물은식품학적으로허용가능한식품첨가제를
포함하는염증성질환의개선용건강기능식품일수있다. [17] 상기염증성질환은염증성장질환，죽상동맥경화,염증성콜라겐혈관질환， 사구체신염，욕창，염증성피부질환，유육종증，망막염 위염,간염,장염，관절염， 편도선염，인후염，기관지염，폐렴,췌장염，패혈증，퇴행성만성염증질환및 신장염으로이루어진군에서선택될수있다.
[18] 상기건강기능식품은울다비오시드 A화합물이조성물총중량에대하여
0.001-50중량%가함유될수있다.
[19] 상기건강기능식품은정제，캡술제，환제및액제로제형화된건강기능식품일 수있다.
[20] 아하본발명을상세하게설명한다.
[21] 본발명은하기화학식 1의울다비오시드 A화합물을유효성분으로함유하는 항염증조성물에관한것이다.
Figure imgf000005_0001
[24] 상기화학식 1의을다비오시드 A화합물은통상적인방법에따라합성할수 있으며 ,약학적으로허용가능한염으로제조될수도있으며，또는유근피 추출물로부터분리，정제될수있다.
[25] 상기유근피는느롭나무과 (Ulmaceae)에속하는느롭나무 (W/ " davidiana var. japonica Nakai)의코르크층을벗긴수피및근피를건조한것이다.
[26] 상기유근피추출물은유근피를물， C1내지 C4의저급알코올또는이들의
흔합용액을용매로하여추출할수있다.상기 C1내지 C4알코올은메탄올, 프로판올,이소프로판올,부탄올및이소부탄올로이루어진군에서선택될수 있다.바람직하게는물로추출한다.
[27] 상기유근피추출물로부터분리된화합물은컬럼크로마토그래피를이용하여 정제할수있다.상가크로마토그래피는실리카겔컬럼크로마토그래피 (silica gel column chromatography), HP-20컬럼크로마토그래피 (HP-20 column
chromatography), RP-18컬럼크로마토그래피 (RP-18 column chromatography), LH-20컬럼크로마토그래피 (LH-20 column chromatography),고성능액체 크로마토그래피 (High-performance liquid chromatography)등에서선택하여 사용할수있다.
[28] 상기항염증조성물은약학적으로허용가능한담체를포함하는염증성질환의 예방또는치료용약학적조성물일수있다.
[29] 상기염증성질환은염증올주병변으로하는질환으로，염증성장질환，
죽상동맥경화，염증성콜라겐혈관질환,사구체신염,욕창，염증성피부질환， 유육종증，망막염，위.염，간염，장염，관절염，편도선염，인후염 ,기관지염，폐렴， 췌장염，패혈증,퇴행성만성염증질환및신장염으로이루어진군에서:선택될 수있다.
[30] 상기염증성장질환은정에만성적으로염증이생기는병으로,허혈성장염， 크론병 (Crohn's disease)및게실염 (intestinal diverticulum)일수있다.
[31] 상기약학적조성물은상기을다비오시드 A화합물이조성물총중량에대하여 0.001~50중량 %，바람직하게는 0.001~40중량 다바람직하게는
0.001-30증량 %로함유될수있다.
[32] 상기약학적조성물은，각각통상의방법에따라산제，과립제，정제，캡슐제， 현탁액，에멀견，시럽，에어로졸,스프레이등의경구형제형,외용제，좌제및 멸균주사용：액의형태로제형화하여사용될수있다.상기약학적조성물에 포함될수있는담체，부형제및희석제로는락토즈，텍스트로즈，수크로스, 솔비를，만니를，자일리를,에리스뫼를，말티를,전분，아카시아고무，알지네이트, 젤라틴，칼슘포스페이트，칼슘실리케이트，셀를로즈,메틸셀롤로즈，미정질 셀를로스，폴리비닐피롤리돈，물,메틸히드록시벤조에이트，
프로필히드록시벤조에이트,탈크，마；!네슴스테아레이트.및광물유를들수 있다.제제화할경우에는보통사용하는층진제，증량제,결합제，습윤제， 붕해계,계면활성제등의희석제또는부형제를사용하여조제된다.경구투여를 위한고형제제에는정제，환제，산제 ,과립제，캡슐제등이포함되며，이러한 고형제제는본발명의울다비오시드 A;화합물에.적어도하나이상의부형제, 예를들면，전분，탄산칼슘，수크로스또는락토즈，젤라틴등을섞어조제된다. 또한단순한부형제이외에마그네슴스테아레이트,탈크같은윤활제들도 사용된다.경구를위한액상제제로는현탁제,내용액제，유제，시럽제등이 해당되는데흔히사용되는단순희석제인물，리퀴드파라핀이외에여러가지 부형제，예를들면습윤제,:감미제，방향제,보존제.등이포함될수있다.비경구 투여를위한제제에는멸균된수용액，비수성용제，현탁제，유제,동결건조제제， 좌제가포함된다.비수성용제，현탁제로는프로필렌글리콜，폴리에틸렌글리콜, 올리브오일과같은식물성기름，에틸올레이트와같은주사가능한에스테르 등이사용될수있다ᅳ좌제의기제로는위텝솔 (witepsol),마크로골，
트원 (tween)-61,카카오지,라우린지,글리세로제라틴등이사용될수있다.
[33] 상기약학적조성물은경구용투여제，스프레이제，겔제，연고제，크림제또는 외용제로제형화된약학적조성물일수있으나，이에한정되지는않는다.
[34] 본발명의약학적조성물의투여량은치료받을대상의연령,성별，체중과， 치료할특정질환또는병라상태，질환또는병리상태의심각도，투여경로및 처방자의판단에따라달라질것이다.이러한인자에기초한투여량결정은 당업자의수준내에있으며，일반적으로투여량은 0.01mg/kg/일내지대략
2000mg/kg/일의범위이다.더바람직한투여량은 lmg/kg/일내지 500mg/kg/일이다. 투여는하루에한번투여할수도있고，수회나누어투여할수도있다.상기 투여량은어떠한면으로든본발명의범위를한정하는것은아니다.
[35] 본발명의약학적조성물은쥐，가축，인간등의포유동물에다양한경로로
투여될수있다.투여의모든방식은예상될수있는데，예를들면，경구,직장 또는정맥,근육，피하，자궁내경막또는뇌혈관내주사및피부도포에의해 투여될수있다:본발명의화합물은독성및부작용이거의없으므로예방 목적으로장기간복용시에도안심하고사용할수있는약제이다.
[36] 또한,상기항염증조성물은식품학적으로허용가능한식품첨가제를
포함하는염증성질환의개선용건강기능식품일수있다.
[37] 상기건강기능식품은울다비오:시드 A화합물이건강기능식품총중량에
대하여 0.001~50중량 %，바람직하게는 0.001~30중량 %，더바람직하게는
0.001 ~10중량 %로함유될수있다.
[38] 상기건강기능식품은정제,캡술제，환제또는액제등의형태를：포함하며，본 발명의울다비오시드 A화합물을첨가할수.있는식품으로는,예를들어,각종 식품류,음료，껌，차，비타민복합제,건강기능성식품류등이있다.
발명의효과
[39] 본발명은유근피 < Jlmus davidiana Planch)추출물로부터분리한을다비오시드 A(Uldavioside A)화합물을유효성분으로함유하는염증성질환의예방또는 치료용조성물에관한것으로，상기울다비오시드 A화합물이염증성
사이토카인의발현을억제하고，염증성피부질환의치료효과가있는것을 확인하였다.
[40] 아를통해，본발명의울다비오시드 A화합물이알레르기성질환，염증성
장질환,죽상동맥경화，염증성콜라겐혈관질환，사구체신염,염증성피부질환， 유육종증，망막염,위염，간염,장염，관절염，편도선염,인후염，기관지염,폐렴， 췌장염，패혈증,욕창，퇴행성만성염증질환，신장염등과같은각종염증성 질환의치료제나건강기능식품으로용이하게이용될수있을것으로기대된다. 도면의간단한설명
[41] 도 1은본발명의울다비오시드 A(Uldavioside A)화합물에대한 ΉΉ
COSY(bold lines)및 ¾-13C HMBC상관관계 (arrow)를나타내는그림이다.
[42] 도 2는본발명의울다비오시드 A화합물의 Raw267.4(A), C2C12(B)및
NIH3T3(C)세포에서의세포독성결과를보여주고있다.
[43] 도 3은본발명의울다비오시드 A화합물처리에따른 Raw264/7, C2C12및
NIH3T3세포에서의염증관련인자인 TNF-a(A), IL-l (B)및 NO(C)의발현량을 확인한결과를보여주고있다.
[44] 도 4는저산소에의한염증반웅에서본발명와울다비오시드 A화합물처리에 따른 iNOS(A)및 ICAM-l, MMP-2와 MMP-9(B)의발현량을확인한결과를 보여주고있다.
[45] 도 5는본발명의을다비오시드 A화합물이포함된크림을욕창환자들에게 처치한결과를보여주는것으로， (A)는항생제내성이나타난욕창 4기환자에 14일동안처치한후의욕창치료효과를, (B)는근막이나타나기시작한욕창 4기환자에 30일처치한결과를, (C)는근막이나타나기시작한욕창 4기환자에 45일：동안처치한욕창치료효과를보여주고있다.
발명의실시를위한최선의 형태;
[46] 이하본발명의바람직한실시예를상세히설명하기로한다.그러나본발명은 여기서설명되는실시예에한정되지않고다른형태로구체화될수도있다.
오히려,여기서소개되는내용이철저하고완전해지고,당업자에게본발명의 사상을층분히전달하기위해제공하는것이다.
[47] <실시예 1.을다비오시드 A화합물의분리 >
[48] 유근피 (fZ/m davidiana Planch)는농가에서건조한것을구입하여사용하였다. 건조된유근피 10g에정제수 1 를첨가한후반연속식저온진공추출기로
25°C에서 12시간동안처리하는것을 3회반복하여유근피추출물을추출하였고， 여과지를이용하여불순물을제거하여유근피열수추출물을얻었다.유근피 열수추출물을 30%메탄올， 50%메탄을， 70%메탄올, 100%메탄올순으로 극성을높여가마등용매용출조건으로하여디아이온 HP-20컬럼
크로마토그래피 (Diaion HP-20 column chromatography)를수행하여 3개의 분획물을얻었다 (Fr. E-1-E-3).이중 Fr. E-1을 70%메탄을등용매로둥용매용출 조건에따른세파덱스 LH-20컬럼크로마토그래피 (sephadex LH-20 column chromatography)을수행하여울다비오시드 A화합물 (9mg)을분리하였다.
[49] <실시예 2.울다비오시드 A화합물의물리화학적구조확인>
[5이 Uldavioside A;
[51] 연갈색분말;
[52] Ή NMR및 13C NMR데이터는하기표 1참조;
[53] ESI-MS [M+H]+m/z 423.1, C20H22O10.
[54] [표 1]
Figure imgf000009_0001
R ( 150 MHz in CD3OD) spectroscopy data
H NMR (600 MHz in CD3OD) spectroscopy data
[55] <실험예 1.동물세포의배양 >
[56] 본발명의울다비오시드 A화합물의활성을확인하기위해대식세포주인
Raw264.7세포，근원세포주 (myoblast)인 C2C12세포,섬유아세포주 (fibroblast)인 NIH3T3세포를 10% FBS(fetal bovine serum), 100U/ ^의페니실린 (penicillin)및 100//g/m£의스트랩토마이신 (streptomycin)이포함되어있는 DMEM(Dulbecco's Modified Eagle's Medium)배지를넣고 37°C, 5% C02배양기에서배양하였다.
[57] <실험예 ;2.울다비오시드 A화합물의세포독성확인 >
[58] 본발명의울다비오시드 A화합물에의한세포독성여부를
MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)어세이방법을 이용해확인하였다.
[59] 상기실험예 1에서배양한 Raw264.7, C2C12및 NIH3T3세포를 48웰
플레이트에웰당 IxlO5개세포가되도록분주하여 24시간동안배양한후， 0.5% FBS, IOOU/I 의페니실린및 10 «g/ni£의스트렙토마이신이포함되어있는 DMEM배지를넣고 18시간동안배양하였다. 18시간배양후，울다비오시드 A 화합물을 ΙμΜ및 10μΜ로처리하고， 24시간동안배양하였다.이때아무것도 처리하지않은 Raw264.7, C2C12및 NIH3T3세포를대조군으로이용하였다. 24시간후에세포에 100 /g/m의농도로 MTT용액을처리하고 37°C에서 3시간 반웅시킨후배양액을제거하고형성된포마잔 (formazan)침전물을
DMSO(dimethyl sulfoxide) 로녹이고 570nm에서흡광도를측정하였고,그 결과를도 2에나타내었다.
[60] 도 2에서보여주듯이，울다비오시드 A화합물을처리한 Raw264.7(2A),
C2C12(2B)및 NIH3T3(2C)세포의생존율이아무것도처리하지않은대조군에 비해증가하였다. ：
[61] 이를통해，본발명의을다비오시드 A화합물이세포독성을나타내지않음을 알수있었다. ：
[62] <실험예 3.울다비오시드 A화합물의염증관련인자의발현확인>
[63] 본발명의울다비오시드 A화합물의처리에따른항염증효과를확인하기위해 염증관련인자인 NO(nitric oxide), TNF-a(tumor necrosis factor-a)및
IL-l(3(interleukin-l(3)의발현량을각각에해당되는 ELISA(enzyme-linked immunosorbent assay)키트를이용하여즉정하였다.
[64] 상기실험예 1에서배양한 Raw264.7, C2C12및 NIH3T3세포를 48웰
플레이트에웰당 lxlO5개세포가되도록분주하여 24시간동안배양한：후, 배지를완전히제거하고, 0.5% FBS가포함된 DMEM배지 (100U/m£의페니실린 및 lOO ^g/me의스트렙토마이신포함)를넣고 18시간동안배양하였다. 18시간 배양후，울다비오시드 A화합물을 ΙμΜ및 ΙΟμΜ이되도록세포에처리하여 1시간동안전반웅시킨다음 2//g/m의 LPS(lipopolysaccharide)를처리하고 24시간배양하였다.이때아무것도처리하지않은 Raw264 , C2C12및 NIH3T3 세포를대조군으로이용하였다. :
[65] 세포배양액에분비된 NO, TNF-α및 IL-Ιβ의발현량을각각의 ELISA:
키트 (ENZO사， USA)를이용하여측정하였다.이때，실험방법은키트에서 제공되는실험방법을토대로진행하였고，그결과를도 3에나타내었다.
[66] 도 3에서보여주듯이， Raw264.7, C2C12및 NIH3T3세포모두에서 LPS처리에 의해증가되었던염증관련인자인 TNF-a(3A), IL-1(3(3B)및 NO(3C)의발현량이 본발명의울다비오시드 A화합물처리농도의존적으로감소되는것을 확인하였다.
[67] 이를통해，본발명의울다비오시드 A화합물이염증관련인자들의발현을 억제함으로써항염증활성을나타낸다는것을알수있었다.
[68] <실험예 4.울다비오시드 A화합물의저산소에의한염증반웅억제활성확인 >
[69] 저산소증은말초혈관등의폐쇄로원활한혈액의흐름이일어나지않는경우에 발생할수있으며，이로인해세포의사멸뿐만아니라염증을유발한다.따라서 본발명의 .울다비오시드 A화합물이저산소에의해유도된염증반웅을 억제하는자확인하고자염증관련인자인 iNOS(inducible nitric oxide synthase), 염증단백질로알려진 ICAM-1 (Intercellular adhesion molecule 1)및염증관련생체 표지인자로사용되고있는 MMP-2(Matrix metalloproteinase-2)및 MMP-9의발현 정도를분석하였다.
[70] 상기실험예 1에서배양한 C2C12및 NIH3T3세포를 100cm플레이트에 80% 정도가차도록분주하여하룻밤동안배양한후,울다비오시드 A화합물을 ΙΟμΜ 및 20μΜ이되도록세포에처리하여 1시간동안전반웅시킨다음,저산소를 유도하기위해질소 94%,이산화탄소 5%，산소 1%조건의저산소 ¾버(1 1)0 & chamber)에넣고 24시간동안배양하였다.이때아무것도처리하지않은세포를 정상대조군으로，저산소를유도하고본발명의울다비오시드 A화합물을 처리하지않은세포를음성대조군으로이용하였다. 24시간후에각각와 세포로부터단백질을회수하여웨스턴블롯방법으로 iNOS, ICAM-1, MMP-2및 MMP-9에해당하는각각의항체를이용하여단백질발현을확인하였고，그 결과를도 4에나타내었다.
[71] 도 4(A)의염증관련인자인 iNOS의발현결과에서보여주듯이，저산소에의해 염증이유발된근원세포에서 iNOS의발현이증가한반면，본발명의
울다비오시드 A를처리한경우에는농도의존적으로저산소에의한 iNOS의 발현이억제되는것을확인하였다.
[72] 또한，도 4(B)의염증단백질인 ICAM-1및염증관련생체표지인자인 MMP-2 와 MMP-9의발현결과에서보여주듯이，저산소에의해염증이유발된 섬유아세포에서 ICAM-1, MMP-2및 MMP-9의발현이증가한반면,본발명의 울다비오시드 A를처리한경우에는농도의존적으로 ICAM-l, MMP-2및 MMP-9의발현이억제되는것을확인하였다.
[73] 이를통해，본발명의울다비오시드 A화합물이쩌산소에의한염증관련
질환의치료효과가있음을알수있었다.
[74] <실험예 5.울다비오시드 A화합물의욕창치료효과확인 >
[75] 욕창이란신체어느부분이든지속적인또는반복적인압력에의해눌린
조직으로혈액순환이안되어그조직미죽어가는상태의질병으로，혈류가 줄어들게되면조직에염증,괴사등이일어나조직손실이：일어난다.따라서 욕창부위에서나타나는염증반웅을억제함으로써욕창을치료할수있다.이에 따라,본발명의울다비오시드 A화합물에의한욕창치료효과를확인하였다.
[76] 욕창 4가환자 10명을대상으로식염수를이용하여욕창부위와주변조직을 세척한후,본발명의울다비오시드 A화합물 0.025중량 %가포함되어있는 크림을욕창부위표면에펴바르고 2차커버드레싱을시행하여욕창부：위를 보호하였다.이와같은방밥으로본발명의울다비오시드 A화합물이포함되어 있는크림을 2일주기로처치하고，욕창이회:복되는정도를관찰하였고，그 결과를도 5에나타내었다.
[77] 도 5에서보여주듯이 ,항생제내성이나타난욕창 4기환자의경우 (5A)에는 크림을처치하고 14일이경과한시점에서욕창부위가감소하는것을
관찰하였다.또한,근막이나타나기시작한욕창 4기환자 (5B및 5C)의경우， 크림을처치하고 30일경과한시점 (5B)또는 45일이경과한시점 (5C)에서 정상적으로육아조직이성장하면서욕창부위가감소되는것을관찰하였다.
[78] 이를통해，본발명의울다비오시드 A화합물이염증억제를통해욕창을
치료할수있음을알수있었다.
[79] <제제예 1.약학적제제 >
[80] 제제예 1-1.겔제형 약학적제제
[81] 조제용기에플루로닉 F-127(BASF Co.제품) 15중량 <¾를 !)11 6.0완충액에넣은 후천천히교반한다음 4°C에서 20시간방치하여맑은점조성의액체를얻었다. 별도의용기에 pH 6.0완층액에본발명의울다비오시드 A화합물 0.025중량 %를 넣은후교반하여용해시 ¾다음조제용기에투입하고교반하였다.또다른 별도의용기에에탄올 4중량 %，파라옥시안식향산메틸에스테르 0.1중량 %및 파라옥시안;식향산프로필에스테르 0.1중량 %를투입한후교반하고용해시킨 다음조제용기에투입하였다.투입된흔합물을 20분동안교반한다음 냉장고에서 4~5시간동안방치함으로써미황색의점조성액을얻었다.얻어진 점조성액에서겔이얻어질때까지서서히가온하였다.
[82] 제제예 1-2.연고제형의 약학적제제
[83] 조：제용기에백색바셀린 15중량 세토스테아릴알콜 10중량 %，
경질유동파라핀 7중량 %및세토마크로골 1.5중량 %를약 650C로가온하여 용융시킨다음용융된액을 100쩨쉬체로여과하였다.별도의용기에정제수를 붓고본발명의울다비오시드 A화합물 0.025중량%를넣어교반하고용해시킨 다음조제용기에투입하였다.또다른별도의용기에 950C의열탕정제수에 파라옥시안식향산메틸에스테르 0.12중량 %，파라옥시안식향산프로필에스테르 0.08중량 %를용해시켜조제용기에투입한다음약 20분동안교반시킨후 호모게나이저로약 20분동안 2500rpm의속도로유화시킨다음유화가완료되면 천천히교반하면서냉각하였다.
[84] 제제예 1-3.정제의제조
[85] 본발명의울다비오시드 A화합물 200g을락토즈 175.9g,감자전분 180g및 콜로이드성규산 32g과흔합하였다.이흔합물에 10%젤라틴용액을첨가시킨 후,분쇄하여 14메쉬체를통과시켰다.이것을건조시키고여기에감자전분 160g,활성 50g및스테아린산마그네슘 5g을첨가해서얻은흔합물을정제로 만들었다ᅳ.
[86] 제제예 1-4.주사액제의제조
[87] 본발명의울다비오시드 A화합물 lg,염화나트륨 0.6g및아스코르브산 O.lg을 증류수에용해시켜서 100 ^를만들었다.이용액을병에넣고 20°C에서 30분간 가열하여멸균사켰다.:
[88] <제제예 1、건강식품제조 >
[89] 제쎄예 2-1.건강식품의 제조
[9이 본발명의울다비오시드 A화합물 200mg,비타민흔합물적량 (비타민 A 아세테이트 70 ，비타민 E l.Omg,비타민 B1 0.13 rag,비타민 B2 0.15mg,비타민 B6 0.5mg,비타민 B12 0.2 /g,비타민 C 10mg,비오틴 lO^g,니코틴산아미드 1.7mg, 엽산 50//g,판토텐산칼슘 0.5mg)및무기질혼합물적량 (황산제 1철 1.75mg, 산화아연 0.82mg,탄산마그네슴 25.3mg，제 1인산칼륨 15mg,게 2인산칼슘 55mg, 구연산칼륨 90mg,탄산칼슘 lOOmg,염화마그네슴 24.8rag)을흔합한다음과립을 제조하고통상와방법에따라건강식품을제조하였다.
[91] 제쎄예 2-2.건강음료의제조
[92] 본발명의울다비오시드: A화합물 1.28mg，꿀 522mg,치옥토산아미드 5rag, 니코틴산아미드 lOmg,염산리보플라빈나트륨 3rag,염산피리독신 2mg,이노시를 30rag,오르토산 : 50mg및물 200i 의조성및함량으로하여통상적인방법을 사용하여음료를제조하였다.

Claims

청구범위 [청구항 1] 하기화학식 1의을다비오시드 A(Uldavioside A)화합물을유효성분으로 함유하는것을특징으로하는항염증조성물.
[화학식 1]
Figure imgf000014_0001
[청구항 2] 제 1항에있어서，
상기항염증조성물은약학적으로허용가능한담체를포함하는염증성 질환의예방또는치료용약학적조성물인것을특징으로하는항염증 조성물. ：
[청구항 3] 제 2항에있어서,
상기염증성질환은염증성장질환，죽상동맥경화，염증성콜라겐혈관 질환，사구체신염,욕창，염증성피부질환,유육종증，망막염，위염，간염， 장염,관절염，편도선염，인후염,기관지염，폐렴，췌장염，패혈증,퇴행성 만성염증질환및신장염으로이루어진군에서선택되는것을특징으로 하는항염증조성물.
[청구항 4] 제 2항에있어서,
상기약학적조성물은울다비오시드 A화합물이:조성물총중량에 대하여 0.001~50증량 %로함유되는것을특징으로하는항염증조성물.
[청구항 5] 제 2항내지제 4항중어느한항에있어서，
상기조성물은경구용투여제，스프레이제，겔제,연고제，크림제또는 외용제로제형화된약학적조성물인것을특징으로하는항염증조성물.
[청구항 6] 제 1항에있어서，
상기항염증조성물은식품학작으로허용가능한삭품첨가제를 포함하는염증성질환의개선용건강기능식품인것을특징으로：하는: 항염증조성물.
[청구항 7] 제 6항에있어서，
상기염증성질환은염증성장질환,죽상동맥경화，염증성콜라겐혈관 질환，사구체신염,욕창，염증성피부질환，유육종증，망막염,위염，간염， 장염，관절염，편도선염,인후염，기관지염，폐렴,췌장염，패혈증，퇴행성 만성염증질환및신장염으로이루어진군에서선택되는것을특징으로 하는항염증조성물.
[청구항 8] 제 6항에있어서,
상기건강기능식품은을다비오시드 A화합물이조성물총중량에대하여
0.001-50중량 %로함유되는것을특징으로하는항염증조성물.
[청구항 9] 제 6항에있어서,
상기건강기능식품은정제,캡술제，환제및액제로제형화된것을 특징으로하는항염증조성물.
PCT/KR2017/006932 2016-07-12 2017-06-30 울다비오시드 a 화합물을 함유하는 항염증 조성물 WO2018012773A1 (ko)

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